In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans

Abstract

Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25-35 kg/m(2), classified as IR or IS by the modified insulin suppression test, consumed deuterated water ((2)H2O) for 4 weeks. Deuterium incorporation into glycerol, palmitate, and DNA indicated TG synthesis, DNL, and adipocyte proliferation, respectively. Net TG synthesis and DNL in adipose cells were significantly lower in IR as compared with IS subjects, whereas adipocyte proliferation did not differ significantly. Plasma FFAs measured during an insulin suppression test were 2.5-fold higher in IR subjects, indicating resistance to insulin suppression of lipolysis. Adipose TG synthesis correlated directly with DNL but not with proliferation. These results provide direct in vivo evidence for impaired TG storage in subcutaneous adipose tissue of IR as compared with IS. Relative inability to store TG in the subcutaneous depot may represent a mechanism contributing to the development of insulin resistance in the setting of obesity.

Keywords: de novo; insulin resistance; lipogenesis; lipolysis; obesity; subcutaneous adipose; triglycerides.

Fig. 1.

TG synthesis and DNL in subcutaneous adipose tissue of obese IS and IR patients. A: Rate of TG synthesis per day (k), based on incorporation of ²H into glycerol moieties and labeling time (P < 0.001). B: Rate of de novo lipogenesis per day (k) based on incorporation of ²H into palmitate (P = 0.004). C: Rate of adipocyte proliferation per day (k) (P = 0.80). D: FFAs at fasting (P = 0.11). E: FFAs at steady-state (insulin infused at 60 μU/ml) (P = 0.059). Mean ± SD shown; P values were generated from log-transformed values and adjusted for BMI using ANCOVA analysis. Circles = male subjects; squares = female subjects.

Fig. 2.

Relationships between adipocyte lipid and cellular dynamics. A: DNL versus log- transformed TG synthesis (r = 0.80; P = 0.006). B: Adipocyte proliferation versus TG synthesis (r = −0.50; P = 0.14). C: Fasting FFAs versus TG synthesis (r = −0.65; P = 0.04). D) FFA at steady-state during SSPG test versus TG synthesis (r = −0.69; P = 0.06). P values generated from log-transformed values, adjusted for BMI using linear multiple regression analysis. Circles = IS; triangles = IR.